Aging is the primary risk factor for neurodegenerative diseases and is associated with increased morbidity and mortality from acute and chronic injuries that lead to cognitive decline. One factor thought to contribute to this loss of resilience is a background of inflammation, however the underlying molecular alterations that lead to inflammation and the therapeutic approaches to improve resiliency are not fully understood (Bennet et al., 1996; Niccoli and Partridge, 2012; Michaud et al., 2013; Moll et al., 2014). Aging is a complex process that involves cellular senescence, a gradual loss of tissue homeostasis and declines in organ function. Aging involves multiple mechanisms that lead to alterations in organism homeostasis. It is becoming clear that the environment of the aged brain or other organs has a profound effect on the function of the brain and the regenerative response of the brain to diseases such as Parkinson's disease, Alzheimer's disease and acute or chronic injuries such as stroke or head injuries. The major contributors to this aging environment are oxidative stress and inflammation. Microglia are one of the main cells in the brain that contribute to both oxidative stress and inflammation. Microglia are constantly sensing the environment and respond differently depending on the signals received. In the aged brain microglia have been reported to be in a primed state where they have an increased response to pro-inflammatory signals and a blunted response to anti-inflammatory signals (Lee et al., 2013; Norden et al., 2014). This priming leads to an environment that is not conducive to neural plasticity related to cognitive function. THE SOLUTION TO THE PROBLEM: The key to modulating microglia in the aged brain is in understanding the complex interactions of proteins involved in upstream regulation of microglial priming. If we identify key regulators this will help us to design new strategies and/or improve current strategies for interventions to improve neural plasticity and cognitive status of elderly Veterans and also improve response to current therapies for neurodegenerative diseases. We propose to examine in depth the proteomic phenotypic response to various M1 and M2 signals in young versus aged microglia. We have already identified 2 major pathways linked to microglial priming under basal conditions in the aged brain, mTORC2 and Nuclear factor erythroid 2- related factor 2 (Nrf2). We will selectively modulate these pathways in microglia to improve synaptic plasticity and cognitive function in the aged brain and the aged brain following injury.